Global population continues to grow at an astonishing rate. Surveys suggest that both genders desire more male contraceptive options. Male hormonal contraceptive regimens that consist of androgens plus a progestin are attractive as they have high efficacy rates, are fully reversible, and, among novel male contraceptives, are the most advanced in clinical development. There are concerns, however, regarding the extra-gonadal effects of exogenous hormone administration in men, particularly surrounding long-term risk for cardiovascular disease (CVD). Data regarding the impact of androgens and progestins on risk factors for CVD are mixed. On the one hand, male hormonal contraceptives lower high-density lipoprotein (HDL), a cardioprotective lipoprotein, and can cause weight gain that might increase insulin resistance over time. In contrast, low levels of serum testosterone are associated with elevated risk for CVD, insulin resistance, and mortality, calling into question the notion that exogenous androgens necessarily increase CVD risk in a dose dependent manner. The overall objective of this proposal is to clarify the impact of male hormonal contraceptives on three important risk factors for CVD in vivo. We will focus on the effects of androgens and progestins on 1) HDL-mediated cholesterol efflux, a key cardioprotective function of HDL, 2) HDL-associated protein composition, and 3) adipose tissue inflammation, a critical mediator of insulin resistance. Emerging data implicates each of these in the pathogenesis of CVD and each is likely modified by exogenous steroids. We will conduct a placebo-controlled trial in healthy men to directly quantify the effects of increasing levels of serum testosterone alone or combine with an effective contraceptive progestin, depomedroxyprogessterone acetatate (DMPA), on human HDL and adipose tissue. To compliment our human study, we will use genetically modified mice to determine whether androgens reduce CVD risk via effects on adipose tissue macrophages, a central cell type in orchestrating adipose tissue inflammation and insulin resistance. The proposed studies will provide both clinical and mechanistic data regarding the impact of androgens and progestins on male metabolism and CVD risk.